Biochemical response to interferon therapy correlates with interferon sensitivity-determining region in hepatitis C virus genotype 1b infection

Biochemical responders maintain normal alanine aminotransferase levels afte r interferon (IFN) therapy despite persistent presence of hepatitis C virus (HCV) RNA in their sera. There have been few reports on predictive factors for biochemical response. A region associated with sensitivity to IFN was identified in the nonstructural protein 5 A of genotype 1b [aa 2209-2248; I FN sensitivity-determining region (ISDR)]. The substitutions in ISDR correl ate with sustained response to IFN. In this report, we assessed the associa tion of ISDR with biochemical response. The sequences of ISDR were determin ed in 62 patients with HCV genotype lb treated by IFN in two randomized con trolled trials. 30 patients had wild ISDR (identical to HCV-J), 20 intermed iate ISDR (1-3 amino acid substitutions compared with HCV-J), and 12 mutant ISDR (four or more amino acid substitutions). All 12 patients with mutant ISDR had a sustained response, while only one of those with wild or interme diate ISDR had a sustained response (P<0.0001). In the 49 patients other th an sustained responders, the patients with intermediate ISDR obtained bioch emical response significantly more frequently (52.6%, 10/19) than those wit h wild-type ISDR (20.0%, 6/30) (P<0.05). Multivariate analysis indicated th e number of substitutions in ISDR as the most important predictor for bioch emical response (discriminant coefficient=1.08, P<0.05) and sustained respo nse (discriminant coefficient=6.13, P<0.0001). In phylogenetic analysis, cl ustering of sustained responders and biochemical responders was observed. T hese results demonstrate that the substitutions in ISDR are the most import ant predictor for biochemical response to IFN in patients infected with gen otype lb as well as for sustained response.